1. Field
This relates to the medical treatment of skeletal (striated) muscle disorders, specifically a method for strengthening and thereby improving the function of such muscles.
2. Prior Art
Many medical conditions are the result of muscles that function improperly. One example is the controlling muscles of eyes. When the strength of the controlling muscles is unequal, the eyes become crossed or misaligned. Another example is that of the extensor muscles of an arm that is held in a flexed position after a stroke of the brain; because such muscles lack proper brain control they are under-active and become weak. Yet another example is that of weakness of a muscle due to atrophy during a period when the nerve to the muscle was temporarily damaged.
Prior Methods of Treatment for Strengthening Muscles
Various methods of strengthening improperly functioning muscles exist. The following are some of these methods.
1. Physical therapy and active exercise to move the limb, activate the attached muscles, and increase the amount of muscle (hypertrophy) is a well-established approach. This method is generally safe, but it is time-consuming, often extending over many weeks or months. It is uncomfortable as the muscle must pull against resistance to gain strength; “no pain, no gain” is a byword of this method. The method is not applicable to many muscles such as those of the eye and the larynx because these muscles are deep in the body so that there is no way to create resistance to the movement as can be done with weights, springs, or the pull of gravity with muscles attached to the limbs or the torso of the body.2. Surgical lengthening or shortening of a muscle or its tendon to tighten or loosen tension is an important method of treatment. It is invasive, painful, carries risks as with all surgery, and requires hospitalization for all but the simplest procedures. The method is not hypertrophic, i.e., it does not strengthen the muscle by increasing the number and size of muscle fibers.3. Botulinum toxin injection into a muscle blocks nerve transmission to the muscle. This can relax overactive muscles, allowing their antagonist muscles to shorten. However, this method does nothing to directly strengthen or enlarge the antagonist muscles.4. Electrical stimulation through electrodes applied to the skin over the muscle can activate and strengthen weak muscles. This method is useful for limb muscles, but no embodiment of this approach can be used for small muscles such as those in the larynx or in the eye due to the depth of these muscles in the body.5. Systemic drugs such as anabolic steroid hormones taken orally, together with exercise, will enlarge and strengthen muscles. However, such drugs are usually illegal and often dangerous to health. Furthermore, they are not selective enough to influence a single target muscle or muscles, as is frequently required in medical treatment.Prior Basic Science Work with Local Anesthetics and Muscles
Of relevance here is the fact that anesthetic drugs are toxic to muscles. Muscles are made up of many protein units (sarcomeres) strung together like the railway cars on a train. Within minutes after exposure to the local anesthetic drug bupivacaine there is breakdown of the connections between these sarcomere units, resulting in irreversible breakdown of the muscle fibers. Sokoll et al. first demonstrated this toxicity to fibers of striated skeletal muscles from exposure to the anesthetic drug bupivacaine. (Sokoll M D, Sonesson B, and Thesleff S., 1968, Denervation changes produced in an innervated skeletal muscle by long-continued treatment with a local anesthetic, Euro J of Pharmacology, 4 (2), pp. 179-187).
Exposure to local anesthetic drugs and study of the resulting degeneration, repair, and regeneration has revealed that anesthetic drugs of both the amino-amide and aceto-amide classes have this toxic effect on muscle fibers. (Bradley W., 1979 Muscle fiber splitting, Muscle Regeneration (pp. 215-232), New York: Raven Press; Hall-Craggs, E. C., 1974, Rapid Degeneration and regeneration of whole skeletal muscle following treatment with bupivacaine (Marcain), Experimental Neurology, 43, 349-358; Hall-Craggs E. C. & Seyan, H. S., 1975 Histochemical changes in innervated and denervated skeletal muscle fibers following treatment with bupivacaine (marcain), Exp. Neurol, 46 (2), 345-354; Libelius, R., Sonesson, B, Stamenovic B. A., and Thesleff, S. 1970 Denervation-like changes in skeletal muscle after treatment with local anaesthetic (Marcaine), J. Anat. 106 (2), 297-309).
Damaged muscles fibers are not repaired but are removed and replaced. (Benoit, P. W., & Belt, W. D., 1970, Destruction and regeneration of skeletal muscle after treatment with a local anaesthetic, bupivacaine (Marcaine). J. Anat, 107 (Pt 3), 547-556).
However, the basic cell membrane, the nerve supply, and the nearby satellite cells remain intact after initial exposure. Within hours of exposure to bupivacaine, inflammatory cells are found in the affected area; these act to clear away the dead muscle fibers. Within one or two days, satellite cells—cells that normally lie dormant within the muscle—begin to proliferate and they regenerate the muscle fibers over the next 7 to 14 days. (Hall-Craggs E. C. B., 1980, Survival of satellite cells following exposure to the local anesthetic bupivacaine (Marcaine), Cell Tissue Res., 209, 131-135; Hall-Craggs E. C. B., 1980, Early ultrastructural changes in skeletal muscle exposed to the local anaesthetic bupivacaine (Marcaine). Br, J. Exp. Path 61, 139-149; Carlson, B. M., Shepard, B., and Komorowski, T. E., 1980 A histological study of local anesthetic-induced muscle degeneration and regeneration in the monkey, J. Orthop. Res., 8 (4): 485-494; Nonaka I., Takagi A., Ishiura, S., Nakase, H. & Sugita, H., 1983, Pathophysiology of muscle fiber necrosis induced by bupivacaine hydrochloride (Marcaine). Acta Neuropathol. (Berl.), 60 (3-4), 167-174; Schultz, E., Jaryszak, D. L., 1985 Effects of skeletal muscle regeneration on the proliferation potential of satellite cells, Mech. Ageing Devel. 30, 63-72; McLoon, L. K., Nguyen, L. T., Wirtschafter, J., 1998, Time course of the regenerative response in bupivacaine injured obicularis oculi muscle. Cell Tissue Res. 294, 439-447).
Several investigators have suggested the use or studied the application of bupivacaine and other anesthetic drugs as treatment to weaken over-active muscles by virtue of their damaging effect. (Park, C. M., Park, S. E., Oh, S. Y., 2004 Acute effects of bupivacaine and ricin mAb35 on extraocular muscle in the rabbit. Curr. Eye Res., 29, 293-301; McLoon, L. K., & Wirtschafter, J. 1993, Regional differences in subacute response of rabbit orbicularis oculi to bupivacaine-induced myotoxicity as quantified with a neural cell adhesion molecule immunohistochemical marker. IOVS 34 (12) 3450-3458.).
U.S. Pat. No. 5,096,930 to Zenka et al., Issued Mar. 17, 1992, specifies use of n-butlyamine, a compound without known anesthetic properties, to aid regeneration of injured muscle. However, as far as I am aware, this method will not strengthen normal muscles.
Three authors have shown that bupivacaine injection in sufficient concentration and volume into the extensor digitorum longus, a muscle in the hind limb of the rat, is followed by enlargement of the muscle beyond its original size. (Rosenblatt, J. D., 1992, A time course study of the isometric contractile properties of rat extensor digitorum longus muscle injected with bupivacaine, Comp. Biochem. Physiol., 101 (2), 361-367; Rosenblatt, J. D., Woods, R. I., 1992, Hypertrophy of rat extensor digitorum longus muscle injected with bupivacaine. A sequential histochemical, immunohistochemical, histological, and morphometric study, J. Anat., 181, 11-27; Plant, D. R., Beitzel, F., & Lynch, G. S., 2005, Length-tension relationships are altered in regenerating muscles of the rat after bupivacaine injection, J. Appl. Physiol., 98 (6), 1998-2003).
In these papers the authors discuss how they measured muscle strength and emphasized that the muscle did not grow stronger, but maintained its original strength as it enlarged.
Local Anesthetics and Eye Muscle Problems
Beginning about 1980, changes were made by a majority of eye surgeons in the US in the technique of inducing anesthesia (blocking pain nerves) and akinesia (blocking the motor nerves to eye muscles to reduce movement) in preparation for cataract surgery. Since those changes were instituted, various eye muscle problems were encountered. Most notably, a misalignment (strabismus) of the injected eye was often seen a few days after the operation, something rarely encountered before. (Rainin, E. A., & Carlson, B. M., 1985 Postoperative diplopia and ptosis, A clinical hypothesis based on the myotoxicity of local anesthetics, Arch. Opthalmol., 103 (9), 1337-1339; Grimmett, M. R., Lambert, S. R., 1992 Superior rectus muscle overaction after cataract extraction, Am. J. Opthalmol., 114 (1), 72-80; Munoz, M., 1994, Inferior rectus muscle overaction after cataract extraction, Am. J. Opthalmol., 118 (5), 664-6.).
The first change made by the eye surgeons was placement of the anesthetic injection alongside the eye (peri-bulbar) instead of behind the eye (retro-bulbar) as was formerly done. The eye muscles are in this peribulbar region and are thus susceptible to exposure to the anesthetic.
The second change was an increase in the volume of the injection from 1.5-2.0 ml to 4.0-7.0 ml to deepen and prolong the anesthesia. It was found that the chance of inducing strabismus increased with increasing injection volume. (Goldchmit M, Scott A B. 1994. Avaliacao da motilidade extrinsca ocular de pacientes facectomizados sob anestesia retrobulbar, Arq. Bras. Oftal., 57, 114-116).
The third change was the use of the amino-amide anesthetic bupivacaine, either alone or added with other anesthetic drugs in the same syringe. Enlarged muscles were shown on magnetic resonance images in some of these cases. The specific pattern of change in the image of the enlarged muscle was interpreted as being fibrous tissue and scarring from the drug injected into the muscle rather than enlargement by growth of new muscle (hypertrophy). (Hamed, L. M. & Mancuso, A., 1991, Inferior rectus muscle contracture syndrome after retrobulbar anesthesia. Opthalmol., 98, 1506-1512.) The amount of the strabismus was often greater looking to the direction away from that of the action of the affected muscle, as if the affected muscle restrained movement. Clinical investigators consistently proposed some form of scarring or fibrosis to explain the altered movements of the injected eye. (Capo, H., Roth, E., Johnson, T., Munoz, M. & Siatkowski, R. M., 1996, Vertical strabismus after cataract surgery, Opthalmology 103 (6), 918-921; Rainin, E. A. & Carlson, B. M., 1985 Postoperative diplopia and ptosis. A clinical hypothesis based on the myotoxicity of local anesthetics. Arch. Opthalmol., 103 (9), 1337-1339; Carlson, B. M., Emerick, S., Komorowski, T. E., Rainin, E. A., Shepard, B. M., 1991, Extraocular Muscle Regeneration in Primates, Opthalmology 99 (4), 582-589.).
All authors have attributed the eye problems encountered (strabismus and muscle enlargement) to inflammation, scarring, fibrosis, and contracture (muscle shortening). No authors or physicians have ever mentioned or reported any increase in muscle strength from these changes. To the best of my knowledge, the deficiencies of the prior methods for muscle strengthening listed above have continued.